title: Control of parasitophorous vacuole expansion by LYST/Beige restricts the intracellular growth of Leishmania amazonensis.
abstract: The intracellular protozoan Leishmania replicates in parasitophorous vacuoles (PV) that share many features with late endosomes/lysosomes. L. amazonensis PVs expand markedly during infections, but the impact of PV size on parasite intracellular survival is still unknown. Here we show that host cells infected with L. amazonensis upregulate transcription of LYST/Beige, which was previously shown to regulate lysosome size. Mutations in LYST/Beige caused further PV expansion and enhanced L. amazonensis replication. In contrast, LYST/Beige overexpression led to small PVs that did not sustain parasite growth. Treatment of LYST/Beige over-expressing cells with vacuolin-1 reversed this phenotype, expanding PVs and promoting parasite growth. The opposite was seen with E-64d, which reduced PV size in LYST-Beige mutant cells and inhibited L. amazonensis replication. Enlarged PVs appear to protect parasites from oxidative damage, since inhibition of nitric oxide synthase had no effect on L. amazonensis viability within large PVs, but enhanced their growth within LYST/Beige-induced small PVs. Thus, the upregulation of LYST/Beige in infected cells functions as a host innate response to limit parasite growth, by reducing PV volume and inhibiting intracellular survival.
authors.affiliation: Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jude
authors.initials: J
authors.lastname: Wilson
authors.forename: Chau
authors.initials: C
authors.lastname: Huynh
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Kennedy
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ward
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.forename: Norma W
authors.initials: NW
authors.lastname: Andrews
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D006790:Host-Parasite Interactions / Q000235:genetics / Q000502:physiology*; D007113:Immunity, Innate / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D007891:Leishmania / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology; D007896:Leishmaniasis / Q000235:genetics / Q000469:parasitology / Q000473:pathology / Q000662:veterinary; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D053141:Organelle Size / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D014617:Vacuoles / Q000382:microbiology / Q000473:pathology*; D033921:Vesicular Transport Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C491133:Lyst protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins; D009569:Nitric Oxide